Abstract Pneumonia is a leading cause of morbidity and mortality across the socioeconomic spectrum. It is also the most frequent cause of acute respiratory distress syndrome (ARDS), due in large part to a harmful imbalance of biological pathways promoting antimicrobial resistance and tissue resilience. The latter is essential for maintaining barrier integrity and limiting alveolar flooding, but host mechanisms protecting the delicate air-liquid interface during pneumonia remain poorly understood. We have previously shown that the IL-6 family cytokine leukemia inhibitory factor (LIF) is critical for limiting acute lung injury in response to infection, and its protective properties do not appear to influence host immunity. A more complete understanding of the biological signals up- and downstream of this cytoprotective factor, which are currently unclear, may provide a unique and important window into pathways that dictate tissue homeostasis without compromising antimicrobial defense. Our published and preliminary results suggest that lung epithelium is both the source and target of LIF during pneumonia, serving as a mechanism of inducible resilience. Initial results also suggest that this response is macrophage-mediated, and that it may involve LIF-dependent changes in the cytoprotective transcriptional co- activator Yes-associated protein (YAP), as well as regulation of the low-density lipoprotein receptor-1 (LOX-1), which can promote injury and cell death. Here we propose the central hypothesis that epithelial integrity is maintained in pneumonic lungs by a macrophage-dependent paracrine LIF axis that promotes tissue resilience. This hypothesis will be tested by pursuing the following 3 aims: Aim 1) Test the hypothesis that LIFR? signaling in lung epithelium prevents acute lung injury during pneumonia; Aim 2) Test the hypothesis that macrophage-epithelial communication initiates the tissue protective circuit mediated by LIF; and Aim 3) Test the hypothesis that LOX-1 induction sensitizes epithelial cells to pneumonic lung injury, and is countered by LIF to fortify tissue resilience. Studies designed to address these aims will employ complementary in vivo and ex vivo strategies to reveal novel pathways of tissue protection in the setting of lung infection. We anticipate that these findings will be leveraged for the development of novel clinical interventions in patients with or at risk for pneumonia and ARDS.